The invention relates to aromatic dicarboxylic acid derivatives, or pharmaceutically-acceptable salts thereof, which possess anti-cell-proliferation activity such as anti-tumor activity and are accordingly useful in methods of treatment of humans and other animals. The invention also relates to processes for the manufacture of said dicarboxylic acid derivatives, to pharmaceutical compositions containing the derivatives and to their use in the treatment of cell-proliferation disorders.
Transcriptional regulation is a major event in cell differentiation, proliferation, and apoptosis. Transcriptional activation of a set of genes determines cell destination and for this reason transcription is tightly regulated by a variety of factors. One of its regulatory mechanisms involved in the process is an alteration in the tertiary structure of DNA, which affects transcription by modulating the accessibility of transcription factors to their target DNA segments. Nucleosomal integrity is regulated by the acetylation status of the core histones. In a hypoacetylated state, nucleosomes are tightly compacted and thus are nonpermissive for transcription. On the other hand, nucleosomes are relaxed by acetylation of the core histones, with the result being permissiveness to transcription. The acetylation status of the histones is governed by the balance of the activities of histone acetyl transferase (HAT) and histone deacetylase (HDAC). Recently, HDAC inhibitors have been found to arrest growth and apoptosis in several types of cancer cells, including colon cancer, T-cell lymphoma, and erythroleukemic cells. Given that apoptosis is a crucial factor for cancer progression, HDAC inhibitors are promising reagents for cancer therapy as effective inducers of apoptosis (Koyama, Y., et al., Blood 96 (2000) 1490-1495).
Several structural classes of HDAC inhibitors have been identified and are reviewed in Marks, P. M., et al., J. Natl. Cancer Inst. 92 (2000) 1210-1216. More specifically, WO 98/55449 and U.S. Pat. No. 5,369,108 report alkanoyl hydroxamates with HDAC inhibitory activity.
It has now been found that certain aromatic dicarboxylic acid derivatives are more potent inhibitors of cell-proliferation than the compounds reported in the aforementioned references. Furthermore, these compounds have HDAC inhibitiory activity.
The invention is directed to an aromatic dicarboxylic acid derivative of the formula I 
denotes a phenyl ring which may be unsubstituted or substituted by 1, 2 or 3 substituents independently selected from a halogen atom, an (1-4C)alkyl-, trifluoromethyl-, hydroxy-, (1-4C)alkoxy-, nitro-, amino-, (1-4C)alkylamino-, di[(1-4C)alkyl]-amino-, (1-4C)alkanoylamino, a (1-3C)alkylenedioxy-group or an acyl group, or alternatively, 
denotes a thiophene ring which may be unsubstituted or substituted by 1 or 2 substituents independently selected from a halogen atom, an (1-4C)alkyl-, trifluoromethyl-, hydroxy-, (1-4C)alkoxy-, nitro-, amino-, (1-4C)alkylamino-, di[(1-4C)alkyl]-amino- or a (1-4C)alkanoylamino, a (1-3C)alkylenedioxy-group or an acyl group, and
R1 and R2 are each independently selected from
a hydrogen atom;
a branched or unbranched (1-14C)alkyl group, which may be unsubstituted or substituted with 1 or several substituents independently selected from the group consisting of a halogen-, hydroxy-, nitro-, amino-, carbocyclic- or a heterocyclic group,
and wherein at a chain length of larger than 2 C-atoms one or several non adjacent C-atoms may be replaced by a corresponding number of heteroatoms such as oxygen, nitrogen or sulfur,
and wherein 2 C-atoms may be bound together by a double or triple bond;
a carbocyclic group;
or a heterocyclic group;
or alternatively, R1 and R2 together with the nitrogen atom to which they are attached form a 3-6 membered ring that may contain additional heteroatoms independently selected from nitrogen, oxygen and sulfur, said ring optionally being annulated to a carbocyclic ring or a heterocyclic ring, said xe2x80x94NR1R2 ring being unsubstituted or optionally substituted by 1, 2, or 3 substituents independently selected from a halogen atom, an (1-4C)alkyl-, trifluoromethyl-, hydroxy-, (1-4C)alkoxy-, aryl-, hetaryl-, arylalkyl, arylalkyloxy-, aryloxy, (1-3C)alkylenedioxy-, nitro-, amino-, (1-4C)alkylamino-, di[(1-4C)alkyl]amino-, (1-4C)alkanoylamino- or an acyl-group.
An alkyl group may be e.g. pentyl, hexyl or 3-methyl-butyl.
A substituted alkyl group may be e.g. benzyl, phenethyl, tetrahydro-furan-2-yl-methyl or 2-cyclohex-1-enyl-ethyl.
An alkyl group where one or several non adjacent atom groups may be replaced by oxygen, nitrogen or sulfur atoms may be e.g. 3-isopropoxy-propyl or 2-methylsulfanyl-ethyl.
An alkyl group wherein 2 atoms may be bound together by a double or triple bond may be e.g. 1-hexinyl or 2-heptenyl.
xe2x80x9cAnnulatedxe2x80x9d as used herein means the fusion of a new ring to a molecule via two new bonds.
A carbocyclic group may be a non-aromatic ring system having 3-7 carbon ring atoms, for example cyclopentane, cyclohexane, cyclohexene or cyclopropane, said ring system being unsubstituted or optionally substituted by 1, 2, or 3 substituents independently selected from a halogen, (1-4C)alkyl-, trifluoromethyl-, hydroxy-, (1-4C)alkoxy-, aryl-, hetaryl-, arylalkyl, arylalkyloxy-, aryloxy, (1-3C)alkylenedioxy-, nitro-, amino-, (1-4C)alkylamino-, di[(1-4C)alkyl]amino-, (1-4)alkanoylamino- or an acyl-group. Said ring atoms optionally may be annulated to an aryl or hetaryl group, to form e.g. an indane or a tetraline. A carbocyclic group as herein defined also may be an aryl group.
An aryl group is a carbocyclic conjugated ring system, for example phenyl, naphthyl, preferably phenyl, which may be unsubstituted or substituted by 1, 2, or 3 substituents independently selected from a halogen atom, an (1-4C)alkyl-, trifluoromethyl-, hydroxy-, (1-4C)alkoxy-, arylalkyloxy-, aryloxy, (1-3C)alkylenedioxy-, nitro-, amino-, (1-4C)alkylamino-, di[(1-4C)alkyl]amino-, (1-4C)alkanoylamino-, carboxyl-, carboxyalkyl- or an acyl-group.
A heterocyclic group may be a non-aromatic ring system having 3-7 ring members, said ring members comprising carbon atoms and one or two hetero atoms independently chosen from nitrogen, oxygen, and sulfur. Examples of heterocyclic groups include piperidino, morpholino, pyrrolidino and piperazino. Said ring system may be unsubstituted or substituted by 1, 2, or 3 substituents independently selected from halogen, (1-4C)alkyl-, trifluoromethyl-, hydroxy-, (1-4C)alkoxy-, aryl-, hetaryl-, arylalkyl, arylalkyloxy-, aryloxy, (1-3C)alkylenedioxy-, nitro-, amino-, (1-4C)alkylamino-, di[(1-4C)alkyl]amino-, (1-4C)alkanoylamino, or an acyl-group. Moreover, said ring members optionally may be annulated to an aryl or hetaryl group, to form e.g. a tetrahydrochinoline, tetrahydroisochinoline or a dihydroindole. A heterocyclic group as defined herein also may be a hetaryl group.
A hetaryl group is either a 5 or 6 membered cyclic conjugated ring system with one or two hetero atoms independently chosen from nitrogen, oxygen, and sulfur, for example pyridinyl, thiophenyl, furyl or pyrrolyl, or an annulated bicyclic conjugated ring system like indolyl-, quinolyl- or isoquinolyl-, which may be unsubstituted or substituted by 1, 2, or 3 substituents independently selected from a halogen atom, an (1-4C)alkyl-, trifluoromethyl-, hydroxy-, (1-4C)alkoxy-, arylalkyloxy-, aryloxy, (1-3C)alkylenedioxy-, nitro-, amino-, (1-4C)alkylamino-, di[(1-4C)alkyl]amino-, (1-4C)alkanoylamino, or an acyl group.
When R1 and R2 together with the nitrogen atom form a 3-6 membered ring which may contain additional heteroatoms independently selected from nitrogen, oxygen and sulfur, it may be e.g. piperidine, piperazine or morpholine.
A suitable value for a substituent when it is a halogen atom is, for example, fluoro, chloro, bromo and iodo; when it is (1-4C)alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl; when it is (1-4C)alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy or butoxy; when it is (1-4C)alkylamino is, for example, methylamino, ethylamino or propylamino; when it is di-[(1-4C)alkyl]amino is, for example, dimethylamino, N-ethyl-N-methylamino, diethylamino, N-methyl-N-propylamino or dipropylamino; when it is (1-4C)alkanoylamino is, for example, formylamido, acetamido, propionamido or butyramido; when it is (1-3C)alkylenedioxy is, for example, methylenedioxy, ethylenedioxy or propylenedioxy; and when it is acyl is, for example, formyl, acetyl, propionyl, benzoyl, or phenylacetyl.
In a preferred embodiment, R1 is hydrogen and R2 has one of the above values. In a more preferred embodiment, R2 is a (1-14C)alkyl group. Most preferrably, R2 is an arylalkylxe2x80x94radical, for example the benzylxe2x80x94radical or substituted benzylxe2x80x94radicals.
Preferred are compounds wherein A denotes a thiophene ring. Even more preferred are compounds wherein the thiophene ring is unsubstituted. Most preferred are compounds wherein two carboxylic moieties are bonded at positions 2 and 5 of a further unsubstituted thiophene ring. Enantiomers, diastereoisomers, racemates and mixtures thereof and pharmaceutically acceptable salts of aromatic dicarboxylic acid derivatives of the formula I are also part of the invention.
The invention is also directed to a pharmaceutical composition comprising a therapeutically effective amount of an aromatic dicarboxylic acid derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as defined above, in association with a pharmaceutically-acceptable diluent or carrier. The pharmaceutical composition may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. In general the above compositions may be prepared in a manner using conventional excipients. The aromatic dicarboxylic acid derivative will normally be administered to a warm-blooded animal at a unit dose within the range 5-5000 mg per square meter body area of the animal, i.e. approximately 0.1-100 mg/kg, and this normally provides a therapeutically-effective dose. A unit dose form such as a tablet or capsule will usually contain, for example 1-250 mg of active ingredient. Preferably a daily dose in the range of 1-100 mg/kg is employed. However the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
According to a further aspect of the present invention there is provided an aromatic dicarboxylic acid derivative of the formula I as defined hereinbefore for use in a method of treatment of the human or animal body by therapy. It has now been found that the compounds of the present invention possess anti-cell-proliferation properties due to inhibition of histone deacetylase. Accordingly the compounds of the present invention provide a method for treating the proliferation of malignant cells. These compounds are useful in the treatment of cancer by providing an anti-proliferative effect, particularly in the treatment of cancers of the breast, lung, colon, rectum, stomach, prostate, bladder, pancreas and ovary. It is in addition expected that a derivative of the present invention will possess activity against a range of leukemias, lymphoid malignancies and solid tumors such as carcinomas and sarcomas in tissues such as the liver, kidney, prostate and pancreas.
Thus according to this aspect of the invention there is provided the use of an aromatic dicarboxylic acid derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as defined herein in the manufacture of a medicament for use in the production of an anti-cell-proliferation effect in a warm-blooded animal such as a human being.
According to a further feature of this aspect of the invention there is provided a method for producing an anti-cell-proliferation effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of an aromatic dicarboxylic acid derivative as defined hereinbefore.
The anti-cell-proliferation treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the aromatic dicarboxylic acid derivative of the invention, one or more other anti-tumor substances, for example those selected from, for example, mitotic inhibitors, for example vinblastine; alkylating agents, for example cis-platin, carboplatin and cyclophosphamide; inhibitors of microtubule assembly, like paclitaxel or other taxanes; antimetabolites, for example 5-fluorouracil, capecitabine, cytosine arabinoside and hydroxyurea, or, for example, intercalating antibiotics, for example adriamycin and bleomycin; immunostimulants, for example trastuzumab; DNA synthesis inhibitors, e.g. gemcitabine; enzymes, for example asparaginase; topoisomerase inhibitors, for example etoposide; biological response modifiers, for example interferon; and anti-hormones, for example antioestrogens such as tamoxifen or, for example antiandrogens such as (4xe2x80x2-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3xe2x80x2-(trifluoromethyl)-propionanilide, or other therapeutic agents and principles as described in, for example, Cancer: Principles and Practice of Oncology, Vincent T. DeVita, Jr., Samuel Hellmann, Steven A. Rosenberg; 5th Ed., Lippincott-Raven Publishers 1997. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of individual components of the treatment. According to this aspect of the invention there is provided a pharmaceutical product comprising an aromatic dicarboxylic acid derivative of the formula I as defined hereinbefore and an additional anti-tumor substance as defined hereinbefore for the conjoint treatment of cancer.
Another object of the present invention is a pharmaceutical composition containing a therapeutically effective amount of one or more compounds of the invention in admixture with pharmaceutically acceptable excipients and/or diluents.
Examples for physiologically acceptable salts of compounds of formula I are salts with physiologically acceptable bases. These salts can be, among others, alkali, earth alkali, ammonium and alkylammonium salts, for example sodium, potassium, calcium, tetra-methyl-ammonium salts.
The compounds of formula I may exist in a racemic mixture. The separation of racemic compounds into their enantiomers can be performed by chromatography on an analytical, semipreparative or preparative scale using suitable optically active stationary phases with suitable eluents. Suitable optically active stationary phases include, but are not limited to, silica (e.g. ChiraSper,Merck; Chiralpak OT/OP, Baker), cellulose esters or carbamates (e.g. Chiracel OB/OY, Baker) or others (e.g. Crownpak, Daicel or Chiracel OJ-R, Baker). Other methods for the separation of enantiomers can also be applied, like the formation of diastereomeric compounds from compounds of the formula I together with other optically active compounds, e.g. camphorsulfonic acid or brucin, and separation of these diastereomeric compounds, followed by the liberation from the optically active agent. Enantiomerically enriched or pure compounds of formula I are also obtainable by the usage of optically active starting materials.
Preparation of the Compounds of the Invention
An aromatic dicarboxylic acid derivative of the formula I, or a pharmaceutically-acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes, when used to prepare an aromatic dicarboxylic acid derivative of the formula I, or a pharmaceutically-acceptable salt thereof, are provided as a further feature of the invention and are illustrated by the following representative examples in which, unless otherwise stated, A, R1 and R2 have any of the meanings defined above. Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying non-limiting examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
(a) One preferred method for the production of compounds of the formula I involves the reaction of compounds of the formula II 
wherein A, R1 and R2 have the meaning defined above and R3 is a (1-4C)alkyl group, preferably a methyl or ethyl group, with hydroxylamine in the presence of a suitable base. The reaction is carried out in an inert solvent or diluent such as methanol or ethanol at temperatures between 0xc2x0 C. and 100xc2x0 C., conveniently at or near ambient temperature, and at a pH between 10 and 12. A suitable base is, for example, an alcoholate, for example, sodium methylate.
Compounds of formula II are prepared from compounds of the formula III wherein A and R3 have the meaning defined hereinbefore 
This reaction typically involves a two-step one-pot procedure. In the first step, the carboxylate of the formula III becomes activated. This reaction is carried out in an inert solvent or diluent, for example, in dichloromethane, dioxane, or tetrahydrofuran, in the presence of an activating agent. A suitable reactive derivative of an acid is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid and a chloroformate such as isobutyl chloroformate; an active ester, for example an ester formed by the reaction of the acid and a phenol such as pentafluorophenol; an active ester formed by the reaction of the acid and N-hydroxybenzotriazole; an acyl azide, for example an azide formed by the reaction of the acid and an azide such as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid and a cyanide such as diethylphosphoryl cyanide; or the product of the reaction of the acid and a carbodiimide such as dicyclohexylcarbodiimide, or the product of the reaction of the acid and bis-(2-oxo-3-oxazolidinyl)-phosphorylchloride. The reaction is carried out between xe2x88x9230xc2x0 C. and 60xc2x0 C., conveniently at or below 0xc2x0 C. In the second step, an amine of the formula HNR1R2 in which R1 and R2 have the meaning defined hereinbefore is added to the solution, at the temperature used for the activation, and the temperature is slowly adjusted to ambient temperature. An appropriate scavenger base like e.g. triethylamine, or diisopropyethlyamine may be added to the reaction mixture. These methods are well known to those skilled in the art. In principle, all methods for the synthesis of amides as used in peptide chemistry as described in e.g. xe2x80x9cMethoden der organischen Chemie (Houben-Weyl)xe2x80x9d Vol. XV/1 and XV/2 are also applicable.
There are quite a few compounds of formula III described in the literature. For example, the prototypic terephthalic monomethylester is described in e.g. Z. Phys. Chem.(Leipzig) 262 (3) (1981) 445-448. It is also commercially available. Thiophene-2,5-dicarboxylic acid monomethyl ester is described in e.g. U.S. Pat. No. 2,680,731. These monoesters are usually prepared by selective saponification of the diester, but other method may be useful as well and are well known to those skilled in the art.
(b) Another preferred method for the preparation of compounds of the formula I is the deprotection of compounds of the formula IV 
wherein Y is a suitable protecting group and A, R1 and R2 have the meaning defined hereinbefore.
Compounds of the formula IV are new and included within the scope of the present invention.
Suitable protecting groups may be the benzyl-, p-methoxybenzyl-, tert.butyloxycarbonyl-, trityl-, or silyl groups such as the trimethylsilyl- or dimethyl-tert.butylsilyl-group. The reactions carried out depend on the type of the protecting group. When the protecting group is a benzyl- or p-methoxybenzyl group, the reaction carried out is a hydrogenolysis in an inert solvent such as an alcohol like methanol or ethanol, in the presence of a noble metal catalyst such as palladium on a suitable carrier such as carbon, barium sulfate, or barium carbonate, at ambient temperature and pressure. When the protecting group is the tert.butyloxycarbonyl-, trityl-, or a silyl group such as the trimethylsilyl- or dimethyl-tert.butylsilyl-group, the reaction is carried out in the presence of acids at a temperature between xe2x88x9220xc2x0 C. and 60xc2x0 C., preferably between 0xc2x0 C. and ambient temperature. The acid may be a solution of hydrochloric acid in an inert solvent such as diethyl ether or dioxane, or trifluoro acetic acid in dichloromethane. When the protecting group is a silyl group such as the trimethylsilyl or dimethyl-tert.butylsilyl group, the reaction can also be carried out in the presence of a fluoride source such as sodium fluoride or tetrabutyl ammonium fluoride in an inert solvent such as dichloromethane. Not necessarily all protecting groups Y are compatible with all groups R1 or R2. In cases where the features of these groups do not allow the usage of a certain protecting group, other protecting groups Y or other methods of preparation need to be applied.
Compounds of formula IV are obtained from the reaction of compounds of formula V 
with a compound of the formula VI 
wherein Y is a suitable protecting group as described above. This reaction typically involves a two-step one-pot procedure. In the first step, the carboxylate of the formula V becomes activated. This reaction is carried out in an inert solvent or diluent, for example, in dichloromethane, dioxane, or tetrahydrofuran, in the presence of an activating agent. A suitable reactive derivative of an acid is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid and a chloroformate such as isobutyl chloroformate; an active ester, for example an ester formed by the reaction of the acid and a phenol such as pentafluorophenol; an active ester formed by the reaction of the acid and N-hydroxybenzotriazole; an acyl azide, for example an azide formed by the reaction of the acid and an azide such as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid and a cyanide such as diethylphosphoryl cyanide; or the product of the reaction of the acid and a carbodiimide such as dicyclohexylcarbodiimide, or the product of the reaction of the acid and bis-(2-oxo-3-oxazolidinyl)-phosphorylchloride. The reaction is carried out between xe2x88x9230xc2x0 C. and 60xc2x0 C., conveniently at or below 0xc2x0 C. In the second step, compound VI is added to the solution, at the temperature used for the activation, and the temperature is slowly adjusted to ambient temperature. These methods are well known to those skilled in the art. In principle, all methods for the synthesis of amides as used in peptide chemistry as described in e.g. xe2x80x9cMethoden der organischen Chemie (Houben-Weyl)xe2x80x9d Vol. XV/1 and XV/2 are also applicable.
Compounds of the formula V are prepared from compounds of the formula II by hydrolysis. The conditions under which the hydrolysis is carried out depend on the nature of the group R3. When R3 is a methyl or ethyl group, the reaction is carried out in the presence of a base, for example, lithium hydroxide, sodium hydroxide, or potassium hydroxide in an inert solvent or diluent, for example, in methanol or ethanol. When R3 is the tert.butyl group, the reaction is carried out in the presence of an acid, for example, a solution of hydrochloric acid in an inert solvent such as diethyl ether or dioxane, or trifluoroacetic acid in dichloromethane. When R3 is the benzyl group, the reaction is carried out by hydrogenolysis in the presence of a noble metal catalyst such as palladium or platinum on a suitable carrier, such as carbon. Not necessarily all methods of hydrolysis are compatible with all groups R1 or R2. In cases where the features of these groups do not allow the usage of a certain method of hydrolysis, other methods of preparation need to be applied.
(c) Another preferred method for the preparation of compounds of the formula I is the reaction of a compound of the formula V with hydroxylamine. This reaction typically involves a two-step one-pot procedure. In the first step, the carboxylate of the formula V becomes activated. This reaction is carried out in an inert solvent or diluent, for example, in dichloromethane, dioxane, or tetrahydrofuran, in the presence of an activating agent. A suitable reactive derivative of an acid is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid and a chloroformate such as isobutyl chloroformate; an active ester, for example an ester formed by the reaction of the acid and a phenol such as pentafluorophenol; an active ester formed by the reaction of the acid and N-hydroxybenzotriazole; an acyl azide, for example an azide formed by the reaction of the acid and an azide such as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid and a cyanide such as diethylphosphoryl cyanide; or the product of the reaction of the acid and a carbodiimide such as dicyclohexylcarbodiimide, or the product of the reaction of the acid and bis-(2-oxo-3-oxazolidinyl)-phosphorylchloride. The reaction is carried out between xe2x88x9230xc2x0 C. and 60xc2x0 C., conveniently at or below 0xc2x0 C. In the second step, hydroxylamine is added to the solution, at the temperature used for the activation, and the temperature is slowly adjusted to ambient temperature. These methods are well known to those skilled in the art. In principle, all methods for the synthesis of amides as used in peptide chemistry as described in e.g. xe2x80x9cMethoden der organischen Chemie (Houben-Weyl)xe2x80x9d Vol. XV/1 and XV/2 are also applicable.
(d) Compounds of formula I can also be prepared with methods of solid phase supported synthesis. Terephthalic acid or 2,5-thiophenedicarboxylic acid is reacted with a hydroxylamine moiety (xe2x80x94Oxe2x80x94NH2) bound to a resin, e.g. a Wang resin (Wang-Oxe2x80x94NH2 resin was supplied by EMC microcollections, Tutbingen) to form a resin-bound hydroxamic acid. The second carbonic acid moiety is reacted with an amine by standard methods of amide formation as described in e.g. xe2x80x9cMethoden der organischen Chemie (Houben-Weyl)xe2x80x9d Vol. XV/1 and XV/2. After this, the hydroxamic acid is liberated from the solid support. This can be done for example with TFA. The crude product can be purified by LC-MS, if necessary.
The invention will now be illustrated in the following non-limiting examples in which, unless otherwise stated:
(i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids such as drying agents by filtration;
(ii) operations were carried out at ambient temperature, that is in the range 18-25xc2x0 C. and under an atmosphere of an inert gas such as argon or nitrogen;
(iii) column chromatography (by the flash procedure) and high pressure liquid chromatography (HPLC) were performed on Merck Kieselgel silica or Merck Lichroprep RP-18 reversed-phase silica obtained from E. Merck, Darmstadt, Germany,
(iv) yields are given for illustration only and are not necessarily the maximum attainable;
(v) melting points were determined using a Mettler SP62 automatic melting point apparatus, an oil-bath apparatus or a Kofler hot plate apparatus.
(vi) the structures of the end-products of the formula I were confirmed by nuclear (generally proton) magnetic resonance (NMR) and mass spectral techniques (Micromass Platform II machine using APCI or Micromass Platform ZMD using electrospray);
(vii) intermediates were not generally fully characterized and purity was assessed by thin layer chromatography;
(viii) the examples were actually performed; and
(viv) the following abbreviations have been used:
DMF, N,N-dimethylformamide;
DMSO, dimethylsulphoxide;
THF, tetrahydrofuran;
MeOH, methanol;
HCl, hydrochloric acid;
NaH, sodium hydride
CH2Cl2, dichloromethane;
H2SO4, sulphuric acid
sat., saturated
sol., solution
rt, room temperature
eq, equivalent